Early Feeding Practices, Growth and Health
The goal of this project is to identify strategies to optimize the nutrition and health of low birth weight (LBW) infants. Studies will determine whether leucine supplementation will enhance lean growth by stimulating protein synthesis and reducing protein degradation in healthy neonatal piglets and during catabolic conditions such as sepsis. We also will determine whether the deficit in lean deposition incurred with continuous feeding, compared to intermittent bolus feeding, during the neonatal period can be recuperated by leucine supplementation or intermittent bolus feeding. Further studies will examine whether citrulline can be used as an early indicator of gut dysfunction in prematurity and if citrulline or arginine supplementation can reduce the incidence of necrotizing enterocolitis (NEC) in the newborn. In other studies, we will examine whether the carbohydrate composition of the formula influences NEC risk by altering the gut microbiome and metabolome. We also will determine the effect of lipid composition and load during provision of total parental nutrition (TPN) on hepatic metabolic function and the risk of the pediatric nutrition-associated liver disease (PNALD). Additional studies will examine the hepatic metabolic dysfunction that accompanies diet-induced obesity and whether this can be prevented by choline supplementation via a liver receptor homolog (LRH-1) mediated process. Taken together, this project will provide novel information that will be directly useful to optimize the nutritional management of LBW infants and improve metabolic health and growth.
The Role of Leptin in Diet-Induced Obesity
Obesity arises when energy intake chronically exceeds energy expenditure. Obesity is associated with several co-morbidities, including type 2 diabetes mellitus, several types of cancer, and cardiovascular disease. Reduction in body weight has a beneficial impact on a number of metabolic and cardiovascular risk factors. Thus, developing effective strategies to fight obesity has the potential to reduce the incidence of a myriad of diseases. Leptin is a potent appetite suppressant which negatively regulates energy balance via activation of leptin receptors, particularly those within the central nervous system. Shortly after leptin was identified, it was established that obesity is commonly associated with increased circulating leptin levels which promote the development of leptin resistance. Despite its key role in the development of obesity and obesity-related metabolic disorders, the mechanisms inducing leptin resistance are not well-understood. Recent studies suggest that disruption of normal circadian rhythms induces leptin resistance, thus promoting obesity. Leptin is also known to significantly impact function of the cardiovascular and immune systems, which may have direct consequences for the development of metabolic syndrome and related co-morbidities. Using a combination of unique investigative tools, including novel genetically-modified mouse models, tissue explant and embryo culture techniques, this project will address multiple aspects of the role leptin plays in the development of obesity. This includes the study of molecular mechanisms which contribute to the development of leptin resistance, and mechanisms by which circadian rhythms regulate leptin expression in adipose tissues and signaling within the hypothalamic arcuate nucleus. A significant body of data also suggests an important role for leptin signaling in the regulation of vascular and hematopoietic cells, which may contribute to altered metabolism and function of these cell types in obesity. We will therefore characterize the functional role of leptin in early hemato-vascular cell development, and study its impact on normal cardiovascular and immune cell function during adult homeostasis.
Diet, Inflammation, and Obesity
The general purpose of this research is enhanced understanding of the influence diet has on the balance between healing and tissue destructive properties of inflammation. The proposed research will use an animal model of diet-induced obesity in mice, and will focus on two general problems associated with obesity: 1) tissue inflammation that may lead to medical complications, and 2) abnormalities in tissue repair, remodeling and wound healing. Specifically, we will analyze two types of white blood cells, lymphocytes and macrophages, and their contributions to the inflammation of skeletal muscle, liver, pancreas, and fat tissues induced after short-term (days) or long-term (months) feeding a high milk fat diet. We will also analyze the influence of a long-term high milk fat diet on the roles of three types of white blood cells (neutrophils, lymphocytes, and macrophages) in tissue remodeling and wound healing. An expected outcome of this research is improved understanding of the relationship between tissue inflammation and diet-induced obesity and insulin resistance that is translatable to human disease.